A Brief Update on the Immune Checkpoint LAG-3

It has been a little over a year since LAG-3 joined PD-1 and CTLA-4 as the only immune checkpoints in the field of #immuno-oncology with approved therapeutics. As a pure-play LAG-3 company, we are pleased to see the increasing attention and focus being paid to this unique gene and how its interaction with MHC Class II can have a profound impact on our immune systems to fight cancer and autoimmune diseases.

Recently described as “the next big kid on the block” by the SVP of Clinical Sciences and Head of Translational Science and Oncology at Regeneron, LAG-3 continues to distance itself from other immune checkpoints. As the immuno-oncology landscape gets more diverse, it is validating to see newer companies to LAG-3 development substantially upscaling their programs this year.

LAG-3 remains unique among the three?immune?checkpoints that have regulatory approvals in that its inhibition on T cells,?as well as its?activation of dendritic cells, engage the immune system to fight?cancer yet?in very different ways.

The vast majority of companies’ use monoclonal or bispecific antibodies to block LAG-3 found on T Cells and boost the immune response against cancer. Immutep pioneered this approach three decades ago in the laboratory of our CSO and founder, Dr. Frédéric Triebel, via the first anti-LAG-3 blocking antibody called 17B4. We continue to have exposure on this side of the LAG-3 landscape via our partnership with Novartis, which has licensed the anti-LAG-3 antibody clinical candidate ieramilimab/LAG525. Additionally, we continue our with our efforts regarding a small molecule approach to blocking LAG-3 that could one day offer the convenience of an oral pill, potentially at a fraction of the cost of existing anti-LAG-3 candidate.

With dozens of active trials evaluating monoclonal and/or bispecific anti-LAG-3 antibodies, including a growing number in Phase 3, clinical data updates around LAG-3 are ensured for years to come and may further cement LAG-3 as the next big immune checkpoint on the block.?

Immutep has currently two wholly owned immunotherapies: our lead clinical candidate in oncology called eftilagimod alpha (efti), and the world’s first agonist to LAG-3 designed to attack the root cause of autoimmune diseases, known as IMP761.?

Efti’s mechanism of action is vastly different from LAG-3 checkpoint inhibitors and focuses on the other side of the LAG-3 & MHC Class II interaction. Through its high-affinity binding to a specific subset of MHC class II molecules found on antigen-presenting cells (APCs), efti drives the activation of APCs and subsequently the activation and proliferation of cytotoxic CD8+ T cells, CD4+ helper T cells, dendritic cells, NK cells, and monocytes to target and kill cancer.?Additionally, efti helps to upregulate the expression of key biological molecules against cancer including the chemokine CXCL10, that recruit various immune cells to tumor sites, and interferon-gamma (IFN-?), which enhance the function of cytotoxic CD8+ T cells and further boost their anti-tumor effects.

Efti continues to build momentum in 2023, in particular in combination with the anti-PD-1 therapy KEYTRUDA? (pembrolizumab) in 1st line non-small cell lung cancer (NSCLC). After being invited to provide oral presentations for our chemo-free IO-IO combination at both ASCO and SITC last year, based upon compelling response rates, strong progression free survival, extended duration of responses, a favorable safety profile, and only 9.6% of patients discontinuing due to adverse events that is consistent with KEYTRUDA? monotherapy, we were excited to announce in May 2023 that these efficacy results have also translated an initial median Overall Survival benefit - the gold standard benchmark in oncology - of 25.0 months in 1L NSCLC patients with >1% PD-L1 expression. This excellent initial survival benefit is above anti-PD-1 monotherapy and other standard-of-care IO-IO, IO-chemo, or IO-IO-chemo combinations in this same patient population (for which efti + anti-PD-1 therapy has received FDA Fast Track designation). We look forward to presenting more mature Overall Survival data at the upcoming ESMO Congress 2023 in October.?

Beyond non-small cell lung cancer, efti has also generated positive clinical data in 2nd line head and neck squamous cell carcinoma (HNSCC) & metastatic breast cancer (MBC).?We look forward to announcing top line results from our randomized and currently recruiting TACTI-003 trial later this year that is evaluating efti + KEYTRUDA? versus KEYTRUDA? alone in 1st line HNSCC patients with varying levels of PD-L1 expression (CPS <1, CPS >1, CPS 1-19 and CPS >20). Additionally, in the lead-in portion of our integrated AIPAC-003 Phase II/III trial in MBC four patients have been receiving their initial 90mg efti injections without experiencing a dose limiting toxicity. We are eager to see if this higher efti dosing can help generate an even greater anti-tumor immune response, along with whether other key adaptations in AIPAC-003 (e.g., administering efti + paclitaxel until disease progression) can further improve upon the encouraging synergistic clinical effects and sustained Quality of Life for women already seen with this IO-chemo combination in a randomized Phase IIb trial.

In addition to these important metastatic cancer indications, we are particularly excited regarding the first ever clinical trial that will test efti in a neoadjuvant setting to target soft tissue sarcoma. All of the clinical benefits seen to date from efti across a variety of clinical trials have come from its subcutaneous delivery driving a systemic anti-cancer effect throughout the body against different metastatic solid tumours. We are eager to see how well efti can perform in this pre-surgery, non-metastatic cancer setting. Furthermore, this is the first time that efti will be combined with radiotherapy and anti-PD-1 therapy (KEYTRUDA?), which hopefully may be an ideal combination to positively impact these patients’ lives. As one of the trial’s principal investigators, Dr. Pawe? Sobczuk, who reached out to Immutep after seeing the clinical results that efti has generated in other immune-compromised oncology indications, stated:

“Soft tissue sarcoma is a rare, aggressive disease in high need of new therapeutic approaches, and we are pleased to begin treating patients with this novel IO-IO-radiotherapy combination and look forward to evaluating the potential synergistic effects of this chemo-free therapy. In particular, efti's sustained activation of antigen-presenting cells, leading to proliferation of activated CD8+ T cells and elevated interferon-gamma levels, may transform the immunosuppressed tumour microenvironment of soft tissue sarcomas into one that enables immune checkpoint inhibitors like pembrolizumab to exert their anti-cancer effect. Additionally, we see synergies between efti and radiotherapy to arm, activate, and proliferate cytotoxic T cells with radiotherapy-induced cancer antigens to target this difficult-to-treat tumour."

Moving onto LAG-3 and autoimmune diseases, we are getting closer and closer to finally bringing the world’s first agonist to LAG-3 called IMP761 into the clinic. The development of this novel immunotherapy was no small feat and took Dr. Triebel and his talented team many years to crack the code to design this LAG-3 agonist antibody.

The field of inhibitory receptor agonists including LAG-3, PD-1, CTLA-4, and others is increasingly gaining attention and being recognized for its potential meaningful role in treating many autoimmune diseases. As a first-in-class immunosuppressive agonist to LAG-3, IMP761 may address the root cause of many autoimmune diseases by silencing autoimmune memory T cells that accumulate at disease sites through increasing LAG-3’s natural downregulation of auto-reactive memory T cells.?

Most recently, we announced our selection of Charles River Laboratories to conduct a GLP toxicology study for IMP761, a key step prior to first-in-human trials. Our goal is to enter the clinic by mid-CY2024 and we look forward to providing more information as we get closer to this important event.?

In summary, as a pure-play LAG-3 company we are quite excited about what the future holds for LAG-3 and its potential positive impact on the lives of patients with cancer and autoimmune diseases by utilizing the power of their own immune systems.?

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Disclaimer:

The ideas, views and opinions expressed in this article represent my own and contain information derived from publicly available sources. No representation or warranty is made as to the accuracy, completeness or reliability of the information.??